A critical tool for human genomics and precision medicine: De novo human genome assembly

A major driver of the current revolution in human genomics and precision medicine is low-cost short read DNA sequencing. This approach involves reading the sequence of tens of millions of short (100-200 base pair) DNA fragments, then assembling these “reads” into longer contiguous sequences. Assembly typically involves mapping an individual read to a unique region of the standard reference human genome. Despite its popularity, short read sequencing has serious weaknesses which prevent about 15% of the known human genome from being analyzed. Because these inaccessible regions include hundreds of genes and tens of thousands of structural variants of potential clinical significance, this contributes to our inability to diagnose the majority of patients thought to have genetic disorders.

These limitations can be largely overcome by assembling the genome of each clinical or research sample individually using long read sequencing, which can read DNA fragments more than a 1000 times longer than those analyzed by short read sequencing. Historically, such de novo assemblies were prohibitively expensive, but with recent improvements in long and ultra-long read sequencing technology, de novo assembly now can be achieved much more cost-effectively.

This project pairs the Center for Human Genomics and Precision Medicine and the UW Biotechnology Center in making now affordable and reliable ultra-long read-based de novo human genome assembly widely available to UW researchers and clinicians so that they can reach these missing regions of the human genome and untangle complex genomic rearrangements in normal tissues and tumors. This resource will put the UW–Madison at the cutting edge of genome science, drive disease gene discovery, and gain novel insights into cancer biology, as well as identify new therapeutic targets for cancer therapy.

PRINCIPAL INVESTIGATOR
Stephen Meyn, professor of pediatrics

CO-INVESTIGATORS
Chris Bradfield, professor of oncology and director of the UW Biotechnology Center

Joshua Hyman, facility director of the UW Biotechnology Center’s DNA Sequencing Facility